Description of the Related Art
ErbB2 is a 185-kDa transmembrane protein kinase receptor with extensive homology to the family of epithelial growth factor receptors (Yarden Y., and Ullrich, A. (1988) Ann. Rev. Biochem. 57:443-478). Aberrant expression of the erbB2 gene may play an important role in neoplastic transformation and progression. In this regard, ectopic expression of erbB2 has been shown to be capable of transforming rodent fibroblasts in vitro (Hudziak, R., et al. (1987) Proc. Natl. Acad. Sci. USA 84:7159-7163). In addition, transgenic mice carrying either normal or mutant erbB2 develop a variety of tumors, predominantly including neoplasms of mammary origin (Muller, W. J., et al. (1988) Cell 54:105-115). Importantly, it has been shown that amplification and/or over-expression of the erbB2 gene occurs in a variety of human epithelial carcinomas, including malignancies of the breast, ovary, gastro-intestinal tract, salivary gland, and lung (Slamon, D. J. et al. (1989) Science 707-712; Semba, K., et al. (1985) Proc. Natl. Acad. Sci. USA 82:6497-6501; Fukushige, S. I., et al. (1986) Mol. Cell Biol. 6:955-958). In the instances of breast and ovarian carcinoma, a direct correlation has been noted between over-expression of erbB2 and aggressive tumor growth with reduced overal patient survival (Hynes, N. E. (1993) Cancer Biology 4:19-26; Gerdes, J., et al. (1984) J. Immunol. 133:1710-1715). There is a lack of effective therapy for erbB2 overexpressing tumors which, in many cases, do not respond well to chemotherapy.
The association of over-expression of the erbB2 gene product with poor clinical prognosis has led to the development of therapeutic strategies to target tumor cells exhibiting increased surface levels of erbB2. Towards this end, monoclonal antibodies (mAbs) have been developed which exhibit high affinity binding to the extracellular domains of the erbB2 protein (Fendly, B. M., et al. (1990) Cancer Research 50:1550-1558; Drebin, J. A., et al. (1988) Oncogene 2:387-394). A subset of these monoclonal antibodies can elicit growth inhibition of erbB2 over-expressing tumor cells both in vitro and in vivo (Drebin, J. A., et al. (1988) Oncogene 2:387-394). Clinical trials in humans have been undertaken which exploit the direct antiproliferative effect of anti-erbB2 monoclonal antibodies (Carter, P., et al. (1992) Proc. Natl. Acad. Sci. USA 89:4285-4289). The utility of antibody based tumor targeting has also been proposed in the context of radiolabeled anti-erbB2 monoclonal antibodies. In addition, antitumor therapies directed at erbB2 have been developed utilizing targeted immunotoxins. These experimental strategies have employed recombinant fusion proteins consisting of various bacterial toxins selectively targeted to tumor cells by virtue of single-chain anti-erbB2 antibody (sFv) moieties.
Alternative to the therapeutic strategies described above that target an antibody to erbB2 expressed on the surface of tumor cells, a number of anti-cancer gene therapy strategies have been developed which employ various methods of molecular ablation of inappropriately or overexpressed genes to revert the transformed phenotype. These strategies have included antisense nucleic acid-mediated inhibition directed at the transcriptional or translational level of gene expression in the context of dominant oncogenes and transdominant mutations to achieve functional inactivation of over-expressed growth factor receptors. Accordingly, given the overexpression of erbB2 in many forms of human cancers, manipulation of the expression and/or function of erbB2 in tumor cells may be beneficial therapeutically. In breast cancer, overexpression of the erbB-2 protein can result from gene amplification and/or transcription factor deregulation.